Association between dystrophin, focal adhesion and muscle fatigability - discussion thread

[Snow Leopard]

(I apologise if this seems to be a little obscure).

Animal models suggest a relationship between dystrophin and muscle fibre fatiguability.

Hyperhomocysteinemia associated skeletal muscle weakness involves mitochondrial dysfunction and epigenetic modifications
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372482/

Fatigue could result from decreased muscle mass and/or structural and metabolic/energy production alterations intrinsic to muscle cells [9]. Structural alterations that lead to progressive muscle weakness are well characterized. Of note are the defects associated with dystrophin complex assembly [10]. Dystrophin anchors the inner cytoskeleton to the outer matrix via a dystrophin complex and is perceived to provide membrane stabilization, especially during rigorous muscle contractions [10-12]. Dystrophin deficiency was proposed to cause muscle membrane injury during exercise and limits exercise capacity [11]. Other deficiencies in structural proteins are also reported [11]. While genetic causes underlying changes in dystrophin and other important structural components, such as truncated protein products and defective splicing, are relatively well characterized, involvement of epigenetic modifications is less well characterized [13].

Correlation of dystrophin–glycoprotein complex and focal adhesion complex with myosin heavy chain isoforms in rat skeletal muscle
https://pubmed.ncbi.nlm.nih.gov/19040708/

Aim: The dystrophin–glycoprotein complex (DGC) and focal adhesion complex (FAC) are transmembrane structures in muscle fibres that link the intracellular cytoskeleton to the extracellular matrix. DGC and FAC proteins are abundant in slow-type muscles, indicating the structural reinforcement which play a pivotal role in continuous force output to maintain posture for long periods. The aim of the present study was to examine the expression of these structures across fast-type muscles containing different myosin heavy chain (MHC) isoform patterns which reflect the fatigue-resistant characteristics of skeletal muscle.
Methods: We measured the expression of dystrophin and b1 integrin (representative proteins of DGC and FAC respectively) in plantaris, extensor digitorum longus, tibialis anterior, red and white portions of gastrocnemius, superficial portion of vastus lateralis and diaphragm, in comparison with soleus (SOL) and cardiac muscle from rats.
Results: The expression of dystrophin and b1 integrin correlated positively with the percentage of type I, IIa and IIx MHC isoforms and negatively with that of type IIb MHC isoform in fast-type skeletal muscles, and their expression was abundant in SOL and cardiac muscle. Conclusion: Our results support the idea that DGC and FAC are among the factors that explain the fatigue-resistant property not only of slow-type but also of fast-type skeletal muscles

Note that. Dystrophin-knock out mice are used as an animal model of Duchenne muscular dystrophy, which is a genetic disorder caused by a SNP in the dystrophin gene.

Also notably, that Urocortins are often used in these animal models to (partially) restore motorfunction such as:
Recovery of Respiratory Function in MDX Mice Co-Treated With Neutralizing interleukin-6 Receptor Antibodies and urocortin-2
https://pubmed.ncbi.nlm.nih.gov/30160301/

Which curiously has some relevance to the Cortene trial.

Now ME or CFS are not muscular dystrophies, with an absence of excess creatine kinase or muscle breakdown products detected in most patients. However that isn't to say that issues couldn't be caused by sensitisation of type 3 sensory fibres due to mechanoreceptor stimulation, perhaps during the post-exercise repair phase due to focal adhesion dysfunction. Alternatively, this dysfunction of focal adhesion could lead to endothelial dysfunction.

Mechanotransduction in striated muscle via focal adhesion kinase
https://hal.archives-ouvertes.fr/hal-00187530v2/document

Gene Expression Profile Exploration of a Large Dataset on Chronic Fatigue Syndrome
https://pubmed.ncbi.nlm.nih.gov/16610953/

Out of 11 identified common pathways, focal adhesion was also found to be related to CFS. This pathway is usually found at the cell membrane where the cytoskeleton interacts with proteins of the extracellular matrix. There is no report implying its relevance to CFS. However focal adhesion directly interacts with several other pathways that are important to CFS, such as cytokine-cytokine receptor interactions, the phosphatidylinositol signalling system, regulation of actin cytoskeleton, apoptosis, and the mitogen-activated protein kinase (MAPK) signalling pathway. Most importantly, all five focal adhesion-interacted pathways were also significantly altered (Table 2).